RS52476B - SYNTHESIS OF DIHIDROTIENO [3,2-d] PYRIMIDINE DIOLES AND SIMILAR PIRIMIDINE DIOLES - Google Patents

Abstract

A process for the preparation of a compound of formula I: comprising: (a) reacting the starting compound of formula II with urea, in the presence of an acid, to give an intermediate of formula IV; and (b) cyclizing the intermediate of formula IV with a base to give the final product of formula I, wherein R 1 and R 2 are independently selected from H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, halogen, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, heterocycloalkoxy, -NO2, -NRR ', haloalkyl, haloalkoxy, -SH, -S-alkyl, -SO2-alkyl, -SO2NH2, -SO2NH-alkyl, and -SO2N (alkyl) 2, wherein R and R' are each independently selected from H or alkyl; wherein Ra is selected from the group consisting of H, halogen, alkyl, and aryl. The application further comprises 20 claims.

Description

SYNTHESIS OF DIHYDROTHIENO[3,2-

d]PYRIMIDINE DIOLS AND SIMILAR

PYRIMIDINE DIOLE

CROSS-REFERENCE TO RELEVANT APPLICATIONS

This application relates to the U.S. Provisional application No. 61/052,816, filed May 13, 2008, the contents of which are incorporated herein by reference.

FIELD OF INVENTION

The present invention relates to an improved process for obtaining dihydrothieno[3,2-pyrimidine diol, especially 6,7-dihydro-thieno[3,2-pyrimidine-2,4-diol] and similar pyrimidine diols. More specifically, the present invention represents a process for obtaining pyrimidine diols in an efficient, high-yield reaction that does not require expensive and potentially unstable intermediates. Pyrimidine diols are useful for a variety of purposes including as intermediates in the synthesis of pharmaceuticals.

DESCRIPTION OF THE RELEVANT STATE OF THE ART

US Patent 3,658,819 describes the preparation of pyranyl-substituted cyclopentapyrimidine-2,4-diol by condensation of 2-ethoxycarbonyl-cyclopentanone with N-(2-tetrahydropyranyl)-urea in the presence of a proton donor and cyclization of the obtained condensation product in the presence of a basic agent.

Such and others. in Bulletin of the Chemical Society of Japan, Vol. 40, p, 2844-2849

(1967) describe the reaction of 2-ethoxycarbonyl-cyclopentanone with urea to give 2-ureido-cyclopentane-carboxylic acid ethyl ester. However, this condensation product is not further cyclized.

Dihydrothienopyrimidines are usually synthesized from dihydrothieno[3,2- d /pyrimidine diols, as described, for example, in U.S. Pat. Patent Publications 2007/0259846 and WO 2006/111549. It turned out to be complex to implement the synthesis of dihydrothieno[3,2-đ]pyrimidine diol intermediates in an efficient reaction that does not require expensive and potentially unstable intermediates and that also results in obtaining the desired product in high yield and purity. For example, the U.S. Patent 3,318,881 discloses the condensation of keto-dihydrothiophene-2-carboxylic acid methyl ester with s-ethylisothiourea to give 2-ethylsulfanyl-6-7-dihydrothieno[3,2-d]pyrimidin-4-ol, which can then be subjected to acid hydrolysis to give dihydrothieno[3,2-d]pyrimidine diol as described in U.S. Pat. Publication of patent No. 2007/0259846. This procedure, however, provides only modest yields, requires the use of s-ethylisothiourea or other s-alkylisothioureas, which is expensive and limited in availability, and produces an unpleasant odor attributed to the release of ethanethiol during acid hydrolysis. Attempts to substitute less expensive urea for s-alkylisothiourea in the condensation reaction were unsuccessful due to poor yields, as reported, for example, by Ohno et al. (1986) in Chem. Pharm Buli. 34:4150.

Other pyrimidines can be synthesized from pyrimidine-2,4-diol, such as 6,7-dihydro-5H-cyclopentapyrimidine-2,4-diol, in modest yields. For example, the parts reported by Sekiya et al. (1980) in Eur. J. Med. Chem. 15, 4: 317 were applied to obtain 2,4-diamino-5,6-polymethylenepyrimidine derivatives for use as hypoglycemic, antihypertensive and anorexigenic agents. However, due to the limitations discussed above, there remains a need in the state of the art to obtain intermediate diols using improved and efficient synthesis procedures.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides an improved, high-yield process for the preparation of dihydrothieno[3,2-d]pyrimidine diols, and similar pyrimidine-2,4-diols. Published procedure for obtaining compounds of formula I:

involves the reaction of the starting compound of formula II with urea, in the presence of an acid, to give the intermediate of formula IV

and cyclization of the intermediate of formula IV with a base to give the final product of formula I.

The acid may be selected from acetic acid, trifluoroacetic acid, perchloric acid, toluene sulfonic acid, hydrobromic acid, hydrochloric acid, sulfuric acid and nitric acid. According to a preferred embodiment, the acid is hydrochloric acid. The base can be selected from the group consisting of metal hydride bases, metal alkoxide bases, and metal phosphate bases. According to a preferred solution, the base is MeONa. According to a further preferred embodiment, the base is NAOH.

According to one solution of the invention, the compound of formula I is 6,7-dihydro-thieno[3,2-d]pyrimidine-2,4-diol (formula la), 6-methyl-6,7-dihydro-thieno[3,2-d]pyrimidine-2,4-diol (formula lb), 6-ethyl-6,7-dihydro-thieno[3,2-d]pyrimidine-2,4-diol (formula Ic), 6-phenyl-6,7-dihydro-thieno[3,2-d]pyrimidine-2,4-diol (formula Id), 6,6-dimethyl-6,7-dihydrothieno[3,2-c(lpyrimidin-2,4-diol (formula le) or 7-Methyl-6,7-dihydro-thieno[3,2-cf|pyrimidine-2,4-diol (formula If).

The preceding and still further features and advantages of the present invention will become apparent upon the following consideration of the detailed description of its characteristic solutions.

DETAILED DESCRIPTION OF THE INVENTION

We will now refer in detail to currently preferred solutions of the invention, which, together with the following examples, serve to explain the principles of the invention. These solutions are described in sufficient detail to enable those skilled in the relevant field to carry out the invention, and it should be understood that other solutions may be used, and that structural, physical and chemical changes may be made without departing from the general idea and scope of the subject invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to whom this invention is intended. readily other methods and materials similar or identical to those described herein may be employed in the practice or testing of the subject invention, preferred methods, apparatus, and materials will now be described.

The following abbreviations will be used here:

Bu = butyl;

HPLC = high performance liquid chromatography;

iPr = isopropyl;

Me = methyl;

NMR = nuclear magnetic resonance;

LCMS (El) = liquid chromatography with mass spectrometry (electron impact)

t = third; and

TLC = thin layer chromatography.

Terms not specifically defined herein shall have the meaning assigned to them by a person skilled in the art in light of the disclosure and context. For example, "C 1-6 alkoxy" is C 1-6 alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy, and hexoxy. All alkyl, alkylene or alkynyl groups will be understood as branched or unbranched where structurally possible and unless otherwise indicated.

Other more specific definitions are given below:

The term "alkyl" refers to a saturated aliphatic radical containing from one to ten carbon atoms or a mono- or polyunsaturated aliphatic hydrocarbon radical containing from two to twelve carbon atoms unless otherwise specified. A mono- or polyunsaturated aliphatic hydrocarbon radical contains at least one double or triple bond, respectively. Examples of "alkyl" include alkyl groups which are straight chain alkyl groups containing from one to eight carbon atoms and branched chain alkyl groups containing from three to ten carbon atoms. Other examples include lower alkyl groups which are straight chain alkyl groups containing from one to six carbon atoms and branched chain alkyl groups containing from three to six carbon atoms. It is to be understood that any combination of terms in which the prefix "alk" or "alkyl" is used refers to analogs of "alkyl" as defined above. For example, terms such as "alkoxy", "alkythio" refer to alkyl groups that are linked to another group by an oxygen or sulfur atom. "Alkanoyl" refers to an alkyl group attached to a carbonyl group (C=O). Any alkyl or alkyl analog described herein will be understood to be optionally partially or fully halogenated.

The term "cycloalkyl" refers to the cyclic analog of an alkyl group, as defined above. Examples of cycloalkyl groups are saturated or unsaturated non-aromatic cycloalkyl groups containing from three to eight carbon atoms, and other examples include cycloalkyl groups having from three to six carbon atoms. Examples of "cycloalkyl" include, for example, cyclopropyl, cyclopentyl, and cyclohexyl.

The term "heterocycloalkyl" refers to a stable 4-8-membered (but preferably, 5- or 6-membered) monocyclic or 8-11-membered bicyclic heterocyclic radical, which may be saturated or unsaturated and is non-aromatic. Each heterocycle contains carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycle can be attached to any ring atom, resulting in a stable structure. Examples of "heterocycloalkyl" include radicals such as pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, azetidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl, dihydro-oxazolyl, 1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide, isothiazolidinyl 1-1,1-dioxide and imidazolidinyl-2,4-dione.

The term "halogen" refers to bromine, chlorine, fluorine or iodine. As used hereinbefore and throughout this application, "nitrogen" and "sulfur" include any oxidized form of nitrogen and sulfur and the quaternized form of any base nitrogen.

The term "ari!" will be understood to mean a 6-12 membered aromatic carbocycle, which may be one ring or multiple rings fused or covalently bonded. The term "aryl" includes, for example, phenyl and naphthyl; other terms containing "aryl" will have the same definition of an aryl component, and examples of such components include: arylalkyl, aryloxy, or arylthio.

The term "heteroaryl" refers to a stable 5-8-membered (but preferably 5- or 6-membered) monocyclic or 8-11-membered bicyclic aromatic heterocyclic radical. Each heterocycle contains carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. A heteroaryl group can be attached to any atom in the ring, resulting in a stable structure. Examples of "heteroaryl" include radicals such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolium, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

The terms "optional" or "optional" mean that the subsequently described process or circumstance may or may not occur, and that the description includes cases in which the particular process or circumstance occurs and cases in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and unsubstituted aryl radicals.

The term "substituted" means that one or more hydrogens on an atom of a group or residue, whether specifically designated or not, have been replaced by selected atoms from the specified group of substituents, provided that the normal valence of the atom is not exceeded and that the substitution results in a stable compound. If it turns out that a bond is crossed by a substituent with a bond connecting two atoms in a ring, then such a substituent can be attached to any atom in the ring. When a substituent is specified without indicating the atom by which such substituent is attached to the rest of the compound, then such substituent may be attached to any atom of that substituent. For example, when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless otherwise indicated, such piperazinyl, piperidinyl, or tetrazolyl group may be attached to the remainder of the compound of the present invention by any atom in such piperazinyl, piperidinyl, or tetrazolyl group. In general, when a substituent or group occurs more than once in any constituent or compound, its definition in each individual case is independent of its definition in every other case. Thus, for example, if a group is shown to be substituted with 0 to 2 R, then such group is optionally substituted with up to two R groups and R is in each case independently selected from a specified list of possible R. Such combinations of substituents and/or variables, however, are permitted only if they result in stable compounds.

The present invention relates to a new strategy for the synthesis of dihydrothieno[3,2-d]pyrimidine diols, and similar pyrimidine-2,4-diols, which give high yield and more efficient reactions and overcomes many of the problems of the prior art related to the large production of dihydrothieno[3,2-c/]pyrimidine diols, and similar pyrimidine-2,4-diols. This strategy provides an efficient synthetic procedure that does not require expensive or potentially unstable intermediates, and that can be performed as a "one-pot" reaction, if desired.

Procedures for the preparation of compounds of formulas (I) and (X) are described herein. The compounds of the invention may be prepared by the general procedures and examples set forth below, and by additional procedures known to those of ordinary skill in the art. The optimal conditions for the reaction and the duration of the reactions may vary depending on the particular reactants used. Unless otherwise indicated, the solvents, temperatures, pressures, and other reaction conditions can be readily selected by one of ordinary skill in the art. Typical procedures are given in the Examples section. The development of the reaction can be followed by conventional techniques such as TLC or HPLC. Intermediates and products can be purified by methods known in the art, including column chromatography, HPLC or recrystallization.

Preferred methods provide procedures for preparing dihydrothieno[3,2-d]pyrimidine diols of formula I, for example:

wherein R<1> and R<2> are independently selected from H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, halogen, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, heterocycloalkoxy, -NO2, -NRR', haloalkyl, haloalkoxy, -SH, -S-alkyl, -SO2-alkyl, -SO2NH2, -SO2NH-alkyl, and -SO2N(alkyl)2, preferably from H, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and -NRR'; and where R and R' are H or alkyl.

As Scheme 1 shows, a solution of the present invention, compounds of formula I can be obtained starting from an acid-catalyzed condensation between an alkyl ester of 3-keto-dihydrothiophene-2-carboxylic acid of formula II, where Ra is alkyl, and urea (III), to obtain an alkyl ester of 3-ureido-dihydrothiophene-2-carboxylic acid of formula IV. The compound of formula IV is then cyclized to give the dihydrothieno[3,2-d]pyrimidine diol of formula I. The cyclization is preferably carried out under basic conditions. Condensation and cyclization reactions can be performed in separate steps, or they can be combined in a "one-pot" process. The product, a compound of formula I, can be further modified by methods known in the art to provide additional compounds, such as dihydrothieno[3,2-d]pyrimidines.

The condensation reaction of compounds of formula II and III occurs in the presence of an acid catalyst, for example, acetic acid, trifluoroacetic acid, perchloric acid, toluene sulfonic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, or nitric acid. According to a preferred embodiment, the acid is hydrochloric acid. An alcohol or a mixture of alcohols can be used as a solvent, for example, methanol, ethanol, isopropanol, n-propanol, butanol, etc. can be used. Methanol is the preferred alcoholic solvent. The reaction can be carried out at temperatures between 0 °C and the reflux temperature of the solvent, and generally requires a period of 0.5 to 24 hours for complete performance, preferably about 2-6 hours, and more preferably about 4-6 or about 3-5 hours. The reaction can be carried out at ambient pressure, or at reduced or elevated pressures.

The previously described reaction gives the alkyl ester of 3-ureido-dihydrothiophene-2-carboxylic acid of formula IV, which can be immediately isolated or left in the reaction vessel due to the "one-pot" procedure. Isolation can be useful when removal of impurities prior to the cyclization process is desired but not necessary.

Whether isolated or not, the compound of formula IV is cyclized, preferably in the presence of a base, in a suitable solvent such as water or an alcohol, for example, methanol, ethanol, isopropanol, n-propanol, butanol, etc. Non-limiting examples of suitable inorganic bases include metal hydrides (eg, NaH), metal hydroxides (eg, NaOH, KOH), metal alkoxides (eg, MeONa, t-BuOK, and Na-tert-amylate), metal carbonates (eg, Na2CO3, K2CO3, Cs2CO3), and metal phosphates (eg, K3PO4). According to the preferred solution, the base is MeONa and the solvent is methanol. According to a further preferred solution, the base is NaOH and the solvent is water. The reaction can be carried out at temperatures between 0 °C and the reflux temperature of the solvent, and generally requires a period of 0.5 to 24 hours for complete completion, preferably about 0.5 to 5 hours, more preferably about 1-3 hours, and even more preferably about 1-2 hours. The reaction can be carried out at ambient pressure. Dihydrothieno[3,2-d]pyrimidine diol of formula I is obtained by the previously described reaction.

The scheme of the previously described reaction (Scheme 1) is more favorable than the known methods of synthesizing dihydrothieno[3,2-c/]pyrimidine diols of formula I, insofar as the yield is higher, more efficient and economical, because urea is used, which is inexpensive and easily available, instead of more expensive reactants such as s-ethylisothiourea hydrobromide. The process in question also avoided the unpleasant odor associated with the release of ethanethiol during known processes. Moreover, the subject process provides another advantage, which is that the alkyl ester of 3-ureido-dihydrothiophene-2-carboxylic acid of formula IV is a solid intermediate of increased stability, which enables its isolation and long-term storage if desired.

Dihydrothiophene carboxylic acid alkyl ester of formula II can be obtained by methods known in the art. For example, a thiol of formula V and an ester of formula VI can be reacted to give a thioether carboxylic acid alkyl ester of formula VII, which can then be cyclized to give a dihydrothiophene carboxylic acid alkyl ester of formula II. A non-limiting exemplary procedure is shown in Scheme 2.

As shown in Scheme 3, a further solution of the present invention relates to compounds of formula X which can be obtained starting from an acid-catalyzed condensation between a compound of formula VIII, where R<a>alkyl, and urea (III), to obtain a compound of formula IX. The compound of formula IX is then cyclized to give the compound of formula X. The cyclization is preferably carried out under basic conditions. Condensation and cyclization reactions can be carried out in separate steps, or they can be combined in a "one-pot" procedure. The product, a compound of formula X, can be further modified by methods known in the art to provide additional pyrimidine diol compounds.

The pyrimidine diols of the previously presented solutions can be used as intermediates for synthesizing pharmaceutical products such as PDE4 inhibitors, in procedures known in the art.

According to one solution of the invention, the process for obtaining compounds of formula I:

contains:

(a) reacting the starting compound of formula II with urea, in the presence of an acid, to give the intermediate of formula IV (b) cyclizing the intermediate of formula IV with a base to give the final product of formula I, where R<1> and R<2> are independently selected from H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, halogen, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, heterocycloalkoxy, -NO2, -NRR', haloalkyl, haloalkoxy, -SH, -S-alkyl, -SO2-alkyl, -SO2NH2, -SO2NH-alkyl, and -SO2N(alkyl)2;

wherein R and R' are each independently selected from H or alkyl; and

wherein R is selected from the group consisting of H, halogen, alkyl, and aryl.

According to a preferred embodiment, R<1> and R<2> are independently selected from H, alkyl, aryl, alkoxy, halogen, haloalkyl, haloalkoxy and -NRR', where R and R' are each independently selected from H or alkyl.

According to another preferred solution, the compound of formula I is

6,7-dihydro-thieno[3,2-d]pyrimidine-2,4-diol, 6-methyl-6,7-dihydro-

thieno[3,2-d]pyrimidine-2,4-diol, 6-ethyl-6,7-dihydro-thieno[3,2-d]pyrimidine-

2,4-diol, 6-phenyl-6,7-dihydro-thieno[3,2-dpyrimidine-2,4-diol, 6,6-dimethyl-6,7-dihydro-thieno[3,2-c(Ipyrimidine-2,4-diol, or 7-methyl-6,7-dihydro-thieno[3,2-d]pyrimidine-2,4-diol.

Preferably, R<a> in the previously shown process is an alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

Additionally, the acid may be selected from acetic acid, trifluoroacetic acid, perchloric acid, toluene sulfonic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, and nitric acid. Preferably, the acid is hydrochloric acid. The base may be selected from the group consisting of metal hydride bases, metal hydroxide bases, metal carbonates, metal alkoxide bases, and metal phosphate bases. Preferably, the base is MeONa or NaOH.

Preferably, in the procedures shown above, the intermediate of formula IV is isolated prior to its cyclization in step (b). The isolated intermediate of formula IV is purified by methods known in the art, including column chromatography, HPLC, or recrystallization. Alternatively, the intermediate of formula IV is not isolated prior to its cyclization in step (b).

According to a further solution, the solvent in step (a) of the previously shown procedures is alcohol or a mixture of alcohols. The alcohol or mixture of alcohols can be methanol, ethanol, isopropanol, n-propanol, butanol or mixtures thereof. According to a still further solution, the reaction presented in step (a) of the preceding procedure is carried out at a temperature between 0°C and the temperature at the reflux of the solvent, and it takes between 0.5 and 24 hours to complete the reaction.

According to a further solution, the solvent in step (b) of the previously presented procedure is water, alcohol or a mixture of alcohols. The alcohol or alcohol mixture may be methanol, ethanol, isopropanol, n-propanol, butanol or mixtures thereof. According to a still further solution, the cyclization reaction presented in step (b) of the preceding procedures is carried out at a temperature between 0°C and the temperature at the reflux of the solvent, and between 0.5 and 24 hours are required to complete the reaction.

EXAMPLES

EXAMPLE 1

Compound III (urea; 2 equiv) was poured into a flask with a stirrer, N2 line and thermocouple, followed by methanol (3 mL/g of compound Ha) and compound lla (1 equiv)

(see Scheme 4). Conc. HCl (0.2 equiv) was poured in at 20-25 °C and the mixture was stirred for 4 hours under reflux. NaOMe (1.2 equiv, 25% solution in MeOH) was introduced at 0°C and the previous mixture was stirred for 1.5 h at reflux and then cooled to 0°C. Conc. HCl was added drop by drop until the pH of the solution reached 2-3, the mixture was stirred for 5-10 min and the resulting solid was collected by filtration. The precipitate was thoroughly washed with water, air-dried for 2-3 hours (with air suction), and then further dried for 12-16 hours in a vacuum oven at 50 °C to obtain compound 1a in 80-85% yield of compound lla.

EXAMPLE 2

methyl ester of 3- ureido- 4, 5- dihydro- thiophene- 2- carboxylic acids

Compound III (urea; 2 equiv) was poured into a vessel with a stirrer, N2 line and thermocouple, followed by methanol (1.5 to 2 mL/g of compound 1a) and compound 1a (1 equiv) (see Scheme 5). Conc. HCl (0.2 equiv) was poured in at 20-25 °C and the mixture was stirred at reflux for 4-6 hours. The reaction mixture was cooled to 0 °C and the resulting solid was collected by filtration. The precipitate was washed with water (twice with 1 mL/g of compound lla) to give compound IVa as a white solid in 95% yield.

95% yield,<1>H NMR (500 MHz, (CD3)2SO) 5 3.10 (dd, 2 H, J= 8.5, 8.5 Hz), 3.50 (dd,2H,J= 8.5, 8.5 Hz), 3.73 (s, 3 H), 6.50-7.20 (bs, 2 H), 9.47 (s, 1 H);<13>C NMR (125 MHz, (CD3)2SO) δ 28.7, 37.8, 52.4, 100.0, 151.6, 154.7, 165.7; LCMS (El) for CtHuNjOsS, (M+H)+ calcd. 203.0, measure. 203.0.

6, 7- dihydro-thienoF3. 2-Qpyrimidine-2, 4-diol

Compound IVa was added to a solution of water (3 mL/mL compound IVa) and NaOH at room temperature. The previous mixture was stirred for 1.5 hours at 85 °C. After cooling to 0 °C, conc. HCl (approx. 1.1 equiv.) was slowly added until the pH of the solution reached 0-1. The mixture was cooled to 0 °C, stirred for 5-10 min and the resulting solid collected by filtration. The precipitate was thoroughly washed with water twice (0.5 mL/g of compound IVa), air-dried for 2-3 hours (air suction), and then further dried in a vacuum oven for 12-16 hours at 50 °C to obtain compound la as a white solid in 95% yield of compound IVa. 95% yield, <1>H NMR (500 MHz, (CD3)2SO) δ 3.11 (dd, 2 H, J= 8.5, 8.5 Hz), 3.31 (dd, 2H,J = 8.5, 8.5 Hz), 11.14 (s, 1 H), 11.38 (s, 1 H); 13CNMR (125 MHz, (CD3)2SO) δ 29.3, 35.4, 108.5, 150.5, 152.4, 160.4; LCMS (El) for C6H7N202S, (M+H)+ calcd. 171.0, measure. 171.0.

EXAMPLE 3

5- methyl- 3- ureido- 4, 5- dihydro- thiophene- 2- carboxylic acid methyl ester

Compound III (urea; 2 equiv) was poured into a vessel equipped with a stirrer, N2 line and thermocouple, followed by methanol (1.5 to 2.0 mL/g of compound llb) and compound llb (1 equiv) (see Scheme 6). Conc. HCl (0.2 equiv) was poured in at 20-25 °C and the mixture was stirred for 4-6 hours under reflux. The reaction mixture was cooled to 0 °C and the resulting solid was collected by filtration. The precipitate was washed with water (twice with 1 mL/g of compound llb) to give compound IVb as a white solid in 93% yield.

93% yield, <1>H NMR (400 MHz, (CD3)2SO) 6 1.32 (d, 3 H,J =6.5 Hz), 3.24 (dd, 1 H,J=6.5, 18.0 Hz), 3.55-3.73 (m, 2 H), 3.72 (s, 3 H), 6.40-7.30 (bs, 1 H), 9.35-9.65 (bs, 1 H);,<3>C NMR (100 MHz, (CD3)2SO) δ 22.8, 40.1, 45.6, 52.3, 99.5, 150.0, 154.7, 165.8; LCMS (El) for C8H13N203S, (M+H)+ calcd. 217.1, measure. 217.6.

6- Methyl- 6. 7- dihydro- thienor3. 2- dlpyrimidine- 2. 4- diol

Compound IVb was added to a solution of water (3 mL/mL compound IVb) and NaOH at ambient temperature. The previous mixture was stirred for 1.5 hours at 85 °C. After cooling to 0 °C, conc. HCl (approx. 1.1 equiv.) was slowly added until the pH of the solution was 0-1. The mixture was cooled to 0 °C, stirred for 5-10 min and the resulting solid was collected by filtration. The precipitate was thoroughly washed with water twice (0.5 mL/g of compound IVb), air-dried for 2-3 hours (with air suction) and then further dried in a vacuum oven for 12-16 hours at 50 °C to obtain compound lb as a white solid in 90% yield of the compound IVb. 90% yield,<1>H NMR (400 MHz, (CD3)2SO) 5 1.39 (d, 3 H,J =6.5 Hz), 2.75 (dd, 1 H, J = 6.5,17.0 Hz), 3.26 (dd, 1H, J= 8.5, 17.0Hz), 3.96 (dddd, 1H, J = 6.5, 17.0 Hz). 5,6.5, 6.5,13.0 Hz), 11.00-11.20 (bs, 1 H), 11.20-11.40 (bs, 1 H); LCMS (El) for C7H9N202S, (M+H)+ calcd. 185.0, measure. 185.1.

EXAMPLE 4

methyl ester of 5- ethyl- 3- ureido- 4, 5- dihydro- thiophene- 2- carboxylic acids

Compound III (urea; 2 equiv.) was poured into a vessel equipped with a stirrer, an N2 line, and a thermocouple, and methanol (1.5 to 2 ml_/g of compound llc) and compound llc (1 equiv.) were added.

(see Scheme 7). Conc. HCl (0.2 equiv) was poured in at 20-25 °C and the mixture was stirred for 4-6 hours under reflux. The reaction mixture was cooled to 0 °C and the resulting solid was collected by filtration. The precipitate was washed with water (twice with 1 mL/g of compound llc) to give compound IVc as a white solid in 93% yield.

93% yield,<1>H NMR (500 MHz, (CD3)2SO) δ 0.93 (t, 3 H, J= 7.3 Hz), 1.52-1.74 (m, 2 H), 3.28 (dd, 1 H,J=6.5,18.0 Hz), 3.53 (dddd, 1 H,J= 6.0, 6.0, 8.5, 8.5 Hz), 3.61 (dd, 1 H,J= 8.5,18.0 Hz), 3.72 (s, 3 H), 6.83 (bs, 2 H), 9.44 (s, 1 H); <13>C NMR (100 MHz, (CD3)2SO) 5 12.8, 29.7, 43.5, 47.3 52.3, 99,3,150.3,154.7,165.7; LCMS (El) for C9H15N203S, (M+H)+ calcd. 231.1, measure. 231.1.

6- ethyl- 6, 7- dihydro- thienof3. 2- d| pyrimidine-2.4-diol

Compound IVc was added to a solution of water (3 mL/mL compound IVc) and NaOH at ambient temperature. The previous mixture was stirred for 1.5 hours at 85 °C. After cooling to 0 °C, conc. HCl (approx. 1.1 equiv.) was slowly added until the pH of the solution was 0-1. The mixture was cooled to 0 °C, stirred for 5-10 min and the resulting solid was collected by filtration. The precipitate was thoroughly washed with water twice (0.5 mL/g of compound IVc), air-dried for 2-3 hours (air suction) and then further dried in a vacuum oven for 12-16 hours at 50 °C to give compound Ic as a white solid in 74% yield of compound IVc.

74% yield, <1>H NMR (500 MHz, (CD3)2SO) δ 0.95 (t, 3 H,J =7.3 Hz), 1.60--1.80 (m, 2 H), 2.81 (dd, 1 H,J=7,0,17.3 Hz), 3.24 (dd, 1 H,J=8.5,17.3 Hz), 3.61 (dddd, 1 H,J=7.0, 7.0, 8.5, 8.5

Hz), 11.10 (s, 1 H), 11.31 (s, 1 H); 13CNMR(100MHz, (CD3)2SO) δ 12.8, 29.8, 40.9, 49.1, 107.7, 149.2, 152.3, 160.3; LCMS (El) for C8H,iN2O2S, (M+H)+ calcd. 199.1, measure. 199.1.

EXAMPLE 5

5-phenyl-3-ureido-4,5-dihydro-thiophene-2-carboxylic acid methyl ester

Compound III (urea; 2 equiv) was poured into a vessel equipped with a stirrer, N 2 line, and thermocouple, followed by methanol (1.5 to 2 mL/g of compound lld) and compound lld (1 equiv) (see Scheme 8). Conc. HCl (0.2 equiv) was poured in at 20-25 °C and the mixture was stirred for 4-6 hours under reflux. The reaction mixture was cooled to 0 °C and the resulting solid was collected by filtration. The precipitate was washed with water (twice with 1 mL/g of compound lld) to give compound IVd as a white solid in 97% yield.

97% yield,<1>HNMR (500 MHz, (CD3)2SO) 5 3.70 (dd, 1 H,J= 8.0,18.0 Hz), 3.74 (s, 3 H), 3.92 (dd, 1 H,J=8.0,18.0 Hz), 4.87 (dd, 1 H,J =8.0, 8.0 Hz), 6.60-7.20 (bs, 2H), 7.25-7.50 (m, 5H), 9.51 (s, 1H); 13C NMR (100 MHz, (CD3)2SO) δ 45.1,48.1, 52.4, 99.4,127.8,128.3,129.5,142.8, 149.5, 154.7, 165.4 (2 signals missing due to overlap); LCMS (El) for C13H15N203S, (M+H)+ calcd. 279.1, measure. 279.1.

6- phenyl- 6. 7- dihydro- thienof3. 2- dlpyrimidine- 2. 4- diol

Compound IVd was added to a solution of water (3 mL/mL compound IVd) and NaOH at ambient temperature. The previous mixture was stirred for 1.5 hours at 85 °C. After cooling to 0 °C, conc. HCl (approx. 1.1 equiv.) was slowly added until the pH of the solution was 0-1. The mixture was cooled to 0 °C, stirred for 5-10 min and the resulting solid was collected by filtration. The precipitate was thoroughly washed with water twice (0.5 mL/g of compound IVd), air-dried for 2-3 hours (with air suction), and then dried in a vacuum oven for 12-16 hours at 50 °C to give compound Id as a white solid in 89% yield of compound IVd. 89% yield, 1H NMR (500 MHz, (CD3)2SO) 3.29 (dd, 1 H,J =8.5,17.5 Hz), 3.51 (dd, 1 H,J=8.5,17.5 Hz), 5.17 (dd,1H, J=8.5, 8.5 Hz), 7.30-7.50 (m, 5H), 11.20 (s, 1 H), 11.42 (s, 1 H); 13C NMR (125 MHz, (CD3)2SO) δ 42.7, 49.6, 107.8, 128.0, 128.7, 129.6, 142.0, 148.5, 152.3, 160.1 (2 signals missing due to overlap); LCMS (El) for C^H^NsOzS, (M+H)+ calcd. 247.1, measure. 247.1.

EXAMPLE 6

methyl ester of 5, 5- dimethyl- 3- ureido- 4, 5- dihydro- thiophene- 2- carboxylic acids

Compound III (urea; 2 equiv) was poured into a vessel equipped with a stirrer, N 2 line, and thermocouple, followed by methanol (1.5 to 2 ml_/g of compound lle) and compound lle (1 equiv) (see Scheme 9). Conc. HCl (0.2 equiv) was poured in at 20-25 °C and the mixture was stirred at reflux for 4-6 hours. The reaction mixture was cooled to 0 °C and the resulting solid was collected by filtration. The precipitate was washed with water (twice with 1 mL/g of compound lle) to give compound IVe as a white solid in 83% yield.

83% yield,<1>HNMR (400 MHz, (CD3)2SO) 5 1.46 (s, 6 H), 3.38 (s, 2 H), 3.71 (s, 3 H), 6.60-7.20 (bs, 2 H), 9.45 (s, 1 H);<l3>C NMR (100 MHz, (CD3)2SO) 6 30.4, 51.6, 52.0, 52.3, 100.2, 149.5, 154.8, 165.8 (1 signal missing due to overlap); LCMS (El) for C9H15N203S, (M+H)+ calcd. 231.1, measure. 231.6.

6. 6- dimethyl- 6, 7- dihydro- thienof3. 2-d1pyrimidine-2, 4-diol

Compound IVe was added to a solution of water (3 mL/mL of compound IVe) and NaOH at ambient temperature. The previous mixture was stirred for 1.5 hours at 85 °C. After cooling to 0°C, conc. HCl (approx. 1.1 equiv.) was slowly added until the pH of the solution was 0-1. The mixture was cooled to 0°C, stirred for 5-10 min and the resulting solid collected by filtration. The precipitate was thoroughly washed with water twice (0.5 ml_/g of compound IVe), air-dried for 2-3 hours (air suction) and then further dried in a vacuum oven for 12-16 hours at 50 °C to give compound le as a white solid in 90% yield of compound IVe. 90% yield, 1 HNMR (400 MHz, (CD 3 ) 2 SO ) δ 1.53 (s, 6 H), 2.95 (s, 2 H), 11.10 (s, 1 H), 11.32 (s, 1 H); 13CNMR(100 MHz, (CD3)2SO) 6 30.7, 49.2, 54.7,108.4,148.2, 152.3, 160.5 (1 signal missing due to overlap); LCMS (El) for CaHuNzOjS, (M+H)+ calcd. 199.1, measure. 199.1.

EXAMPLE 7

4- Methyl- 3- ureido- 4, 5- dihydro- thiophene- 2- carboxylic acid methyl ester

Compound III (urea; 2 equiv) was poured into a vessel equipped with a stirrer, N2 line, and thermocouple, followed by methanol (1.5 to 2 mL/g of compound llf) and compound llf (1 equiv)

(see Scheme 10). Conc. HCl (0.2 equiv) was poured in at 20-25 °C and the mixture was stirred at reflux for 4-6 hours. The reaction mixture was cooled to 0 °C and the resulting solid was collected by filtration. The precipitate was washed with water (twice with 1 mL/g of compound llf) to give compound IVf as a white solid in 48% yield.

48% yield, 1HNMR (500 MHz, (CD3)2SO) 5 1.16 (d, 3 H, J= 7.0 Hz), 2.75 (d, 1 H,J=11.0 Hz), 3.20 (dd, 1 H,J=7.5, 11.0 Hz), 3.73 (s, 3 H), 4.35-4.43 (m, 1 H), 6.50-7.20 (m, 2 H), 9.40 (s, 1 H); 13C NMR (125 MHz, (CD3)2SO) δ 16.7, 36.0, 42.0, 52.4, 98.8, 154.3, 155.7, 166.0; LCMS (El) for C8Hi3N2O3S, (M+H)+ calcd. 217.1, measured 217.1.

7- methyl- 6. 7- dihydro- thienor3. 2- dlpyrimidine- 2, 4- diol

Compound IVf was added to a solution of water (3 mL/mL compound IVf) and NaOH at room temperature. The previous mixture was stirred for 1.5 hours at 85 °C. After cooling to 0°C, conc. HCl (approx. 1.1 equiv.) was slowly added until the pH of the solution was 0-1. The mixture was cooled to 0°C, stirred for 5-10 min and the resulting solid collected by filtration. The precipitate was thoroughly washed with water twice (0.5 mL/g of compound IVf), air-dried for 2-3 hours (air suction), and then further dried in a vacuum oven for 12-16 hours at 50 °C to obtain compound If as a white solid in 89% yield of compound IVf. 89% yield, 1H NMR (500 MHz, (CD3)2SO) δ 126 (d, 3 H,J=7.0 Hz), 2.92 (dd, 1 H,J = 5.0,11.0 Hz), 3.34-3.42 (m, 1 H), 3.52 (dd, 1 H, J= 8.5,11.0 Hz), 11.17 (s, 1 H), 11.34 (s, 1 H); LCMS (El) for C7HgN2O2S, (M+H)+ calcd. 185.0, measure. 185.2.

EXAMPLE 8

2-Ureido-cyclopent-1-encarboxylic acid methyl ester

Compound III (urea; 2 equiv) was poured into a vessel equipped with a stirrer, N 2 line, and thermocouple, followed by methanol (1.5 to 2 mL/g of compound IIIa) and compound IIIa (1 equiv) (see Scheme 11). Conc. HCl (0.2 equiv) was poured in at 20-25 °C and the mixture was stirred at reflux for 4-6 hours. The reaction mixture was cooled to 0 °C and the resulting solid was collected by filtration. The precipitate was washed with water (twice with 1 mL/g of compound VIIIa) to give compound IXa as a white solid in 100% yield.

100% yield, <1>H NMR (400 MHz, (CD3)2SO) 5 1.79 (dt, 2 H, J - 7.6, 7.6 Hz), 2.43 (t, 2 H, J= 7.6 Hz), 3.06 (t, 2 H, J=7.6 Hz), 3.68 (s, 3 H), 6.5-7.0 (bs, 2 H), 9.44 (s, 1 H); <13>C NMR (100 MHz, (CD3)2SO) δ 21.6, 29.0, 34.9, 51.4, 102.3, 155.1, 157.9, 167.8; LCMS (El) for C8H13N2O3, (M+H)+ calcd. 184.1, measure. 185.0.

6, 7- dihydro- 5H- cyclopentapyrimidine- 2. 4- diol

Compound IXa was added to a solution of water (3 mL/mL compound IXa) and NaOH at ambient temperature. The previous mixture was stirred for 1.5 hours at 85 °C. After cooling to 0°C, conc. HCl (approx. 1.1 equiv.) was slowly added until the pH of the solution was 0-1. The mixture was cooled to 0°C, stirred for 5-10 min and the resulting solid collected by filtration. The precipitate was thoroughly washed with water twice (0.5 mL/g of compound IXa), air-dried for 2-3 hours (air suction), and then further dried in a vacuum oven for 12-16 hours at 50 °C to give compound Xa as a white solid in 99% yield of compound IXa. 99% yield, <1>H NMR (500 MHz, (CD3)2SO) δ 1.99 (dt, 2 H,J=7.5, 7.5 Hz), 2.48 (t, 2 H,J =7.5 Hz), 2.67 (t, 2 H, J = 7.5 Hz), 10.70 (bs, 1H), 11.05 (bs, 1H); ,13C NMR (100 MHz, (CD3)2SO) δ 21.9, 27.3, 31.9, 110.5, 153.2, 157.0, 162.9; LCMS (E1) for C7H9N2O2, (M+H)+calcd. 153.1, measure. 153.3.

methyl ester of 2- ureido- 3H- indene- 1- carboxylic acids

Compound III (urea; 2 equiv) was poured into a vessel equipped with a stirrer, N 2 line, and thermocouple, followed by methanol (1.5 to 2 mL/g of compound IIIlb) and compound IIIlb (1 equiv) (see Scheme 11). Conc. HCl (0.2 equiv) was poured in at 20-25 °C and the mixture was stirred at reflux for 4-6 hours. The reaction mixture was cooled to 0 °C and the resulting solid was collected by filtration. The precipitate was washed with water (twice with 1 mL/g of compound VIIlb) to give compound IXb as a white solid in 72% yield.

72% yield, <1>H NMR (500 MHz, (CD3)2SO) h 3.91 (s, 3 H), 4.21 (s, 2 H), 6.8-7.4 (bs, 2 H), 7.09 (ddd, 1 H, J=1.5, 7.5, 7.5 Hz), 7.25 (ddd, 1H, J=1.5, 7.5, 7.5 Hz), 7.40 (d, 1 H, J=7.5 Hz), 7.71 (d, 1H, J= 7.5 Hz), 10.00 (bs, 1 H); <13>C NMR (100 MHz, (CD3)2SO) 5 40.5, 51.9, 105.4, 120.9, 123.8, 124.1, 127.3, 137.1, 140.6, 154.8, 161.5, 167.0; LCMS (El) for C12H13N2O3l (M+H)+ calcd. 233.1, measure. 233.2.

9H-indenof2. 1- dlpyrimidine- 2, 4- diol

Compound IXb was added to a solution of water (3 mL/mL compound IXb) and NaOH at room temperature. The previous mixture was stirred for 1.5 hours at 85 °C. After cooling to 0°C, conc. HCl (approx. 1.1 equiv.) was slowly added until the pH of the solution was 0-1. The mixture was cooled to 0°C, stirred for 5-10 min and the resulting solid collected by filtration. The precipitate was thoroughly washed with water twice (0.5 ml_/g of compound IXb), air-dried for 2-3 hours (air suction), and then further dried in a vacuum oven for 12-16 hours at 50 °C to give compound Xb as a white solid in 93% yield of compound IXb. 93% yield, <1>H NMR (500 MHz, (CD3)2SO) δ 3.84 (s, 3 H), 7.18 (dd,1 H, J= 7.5, 7.5 Hz), 7.31 (dd, 1H,J= 7.5, 7.5 Hz), 7.47 (d, 1 H,J =7.5 Hz), 7.73 (d, 1 H,J= 7.5 Hz), 11.13 (bs, 1H), 11.79 (bs, 1H); 13C NMR (100 MHz, (CD3)2SO) δ 36.6, 111.6, 120.3, 125.0, 125.1, 127.8, 137.6, 139.6, 152.4, 160.0, 161.3; LCMS (El) for CnHgN^, (M+H)+ calcd. 201.1, measure. 201.1.

The foregoing description, drawings, and examples are merely illustrative of preferred solutions that meet the objectives, features, and advantages of the present invention. The subject invention is not intended to be limited to illustrative solutions.

Claims (1)

1: Process for obtaining compounds of formula I: comprising: (a) reacting the starting compound of formula II with urea, in the presence of an acid, to give the intermediate of formula IV (b) cyclizing the intermediate of formula IV with a base to give the final product of formula I, where R<1> and R<2> are independently selected from H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, halogen, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, heterocycloalkoxy, -NO2, -NRR', haloalkyl, haloalkoxy, -SH, -S-alkyl, -SO2-alkyl, -SO2NH2, -SO2NH-alkyl, and -SO2N(alkyl)2; wherein R and R' are each independently selected from H or alkyl; and wherein R is selected from the group consisting of H, halogen, alkyl, and aryl. 2: The process of claim 1, wherein R1 and R<2> are independently selected from H, alkyl, aryl, alkoxy, halogen, haloalkyl, haloalkoxy and -NRR', wherein R and R' are each independently selected from H or alkyl. 3: Process according to claim 1 or 2, wherein R<a>alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. 4: Process according to one of claims 1 to 3, wherein the acid is selected from acetic acid, trifluoroacetic acid, perchloric acid, toluene sulfonic acid, hydrobromic acid, hydrochloric acid, sulfuric acid and nitric acid. 5: Process according to one of claims 1 to 4, wherein the acid is hydrochloric acid. 6: The method according to one of claims 1 to 5, wherein the base is selected from the group consisting of metal hydride bases, metal hydroxide bases, metal carbonates, metal alkoxide bases, and metal phosphate bases. 7: The process according to claim 6, wherein the base is MeONa. 8: Process according to claim 6, wherein the base is NaOH. 9: Process according to claim 1, wherein the compound of formula I is 6,7-dihydro-thieno[3,2-d]pyrimidine-2,4-diol; 6-methyl-6,7-dihydro-thieno[3,2- d ]pyrimidine-2,4-diol; 6-ethyl-6,7-dihydro-thieno[3,2-d]pyrimidine-2,4-diol; 6-phenyl-6,7-dihydro-thieno[3,2-d]pyrimidine-2,4-diol; 6,6-dimethyl-6,7-dihydro-thieno[3,2- d /pyrimidine-2,4-diol; or 7-methyl-6,7-dihydro-thieno[3,2-c]pyrimidine-2,4-diol. 10: The process of claim 1, wherein the intermediate of formula IV is isolated prior to its cyclization in step (b). 11: The process of claim 10, wherein the isolated intermediate of formula IV is also purified by a process known in the art. 12: The method according to claim 11, wherein the method is known in the art of column chromatography, HPLC or recrystallization. 13: The process of claim 1, wherein the intermediate of formula IV is not isolated prior to its cyclization in step (b). 14: The process of claim 1, wherein the solvent in step (a) is an alcohol or a mixture of alcohols. 15: Process according to claim 14, wherein the alcohol or mixture of alcohols is methanol, ethanol, isopropanol, n-propanol, butanol or mixtures thereof. 16: The process according to claim 14, wherein the reaction is carried out at a temperature between 0°C and the reflux temperature of the solvent. 17: The method of claim 14, wherein step (a) takes between 0.5 hours and 24 hours to complete. 18: The process of claim 1, wherein the solvent in step (b) is water, alcohol or a mixture of alcohols. 19: Process according to claim 18, wherein the alcohol or mixture of alcohols is methanol, ethanol, isopropanol, n-propanol, butanol or mixtures thereof. 20: The process according to claim 18, wherein the cyclization reaction (b) is carried out at a temperature between 0°C and the reflux temperature of the solvent. 21: The process according to claim 18, wherein the cyclization reaction (b) takes between 0.5 hours and 24 hours to complete.